Our laboratory has four major areas of interest.
Mammalian
Genomics Our laboratory has been involved in the mapping
and sequencing of the human/ and mouse genomes using yeast artificial
chromosomes and later, bacterial artificial chromosomes. We made
a detailed physical map of human chromosome 12. In collaboration
with the Genome Center at Baylor College of Medicine, we have finished
the sequence of this chromosome. We were involved in mapping and
cloning several human disease genes on this chromosome. They include,
Noonan syndrome, Darier disease, Cornea plana and Holt-Oram syndrome.
We have also contributed to the draft sequence of the mouse genome.
We use the mapping and sequencing expertise to clone new human disease
genes.
Molecular Etiology of Velo-Cardio-Facial/
DiGeorge Syndrome (VCFS/DGS) VCFS/DGS is a relatively common
human syndrome. Children with VCFS/DGS present with a spectrum of
phenotypes including cardio-vascular defects, immunological abnormalities,
muscle weakness, hypernasal speech and learning disabilities. As
they grow older, a large portion of them also develop psychiatric
illness. The disorder results from haploinsufficiency of a 3 Mb
region on human chromosome 22q11. We constructed detailed maps of
this region and identified genes encoded by the DNA in 22q11. Using
genetic engineering technologies, we made mice that carry a deletion
in a region of the genome that corresponds to human 22q11. These
mice exhibit some of phenotypes observed in VCFS/DGS patients. Using
BAC complementation, we narrowed the critical region and identified
a candidate gene, Tbx1. When Tbx1 is mutated, the mice develop vascular
defects similar to those seen in human VCFS/DGS patients. We are
now interested in understanding how haploinsufficiency of Tbx1 causes
the major phenotypes of VCFS/DGS.
Mouse
Models for Human Cancer We have a long-standing program
to understand the role of genes involved in human colorectal cancer.
Towards this goal, we used genetic engineering technologies to make
mice with mutations in each of a large set of genes suspected to
be involved in the initiation and progression of gastrointestinal
cancer. These genes include, APC, MCC, N-RAS, SMAD2, SMAD4, MSH2,
MSH3, MSH4, MSH5, MSH6, MLH1, FEN1 and ARVCF. Mice with mutations
in Apc, Msh2, Msh6 and Mlh1 show a cancer predisposition phenotype.
Mice with mutations in Smad4, Msh3, Fen1 and Arvcf do not develop
tumors but mutations in these genes increase tumor susceptibility
in Apc mutant mice. Mice with mutations in MlH1, Msh4 and Msh5 are
sterile. The sterility is caused by meiotic arrest. We are interested
in examining the roles of these and other genes in cancer initiation
and progression.
Noonan Syndrome (NS). Noonan
syndrome (NS) is an autosomal dominant disorder affecting an estimated
1/100 (mildly affected) to 1/1000-2,500 (severely affected) people.
There is considerable heterogeneity in expression. Affected patients
have typical facial features and may have congenital heart disease,
motor delay, learning problems or mental retardation, hearing loss,
visual problems, chest deformity, scoliosis, undescended testes,
pubertal delay, short stature, or a bleeding disorder (Mendez 1985,
Noonan 1994).
Early studies found that between 45% and 50% of individuals with Noonan syndrome
have identifiable mutations in the PTPN11 gene (Tartaglia 2001, Tartaglia 2002).
Preliminary genotype phenotype correlations demonstrate that familial cases of
NS and patients with pulmonary valve stenosis are more likely to have a PTPN11
mutation (Tartaglia 2002).
The purpose of our research is to identify how many patients with Noonan
syndrome, patients with a Noonan-like syndrome, or patients with isolated
pulmonary valve disease or hypertrophic cardiomyopathy have a mutation in the
PTPN11 gene. The study involves collecting DNA samples for PTPN11 testing,
completing physical exams, reviewing past medical histories and compiling family
histories of all participants. The test results and medical information
obtained from participants in the study will be used to make phenotype genotype
correlations in the mutation positive patients. These correlations will
hopefully improve diagnosis, treatment and counseling.
References
NCBI
PubMed search of "R. Kucherlapati"
Montgomery, K.T., Lee, E., Miller,
A., Lau, S., Shim, C., Decker, J., Chiu, D., Emerling, S., Sekhon,
M., Kim, R., Lenz, J., Han, J., Ioshikhes, I., Renault, B., Marondel,
I., Yoon, S.-J. K., Song, K., Murty, V.V.V.S., Scherer, S., Yonescu,
R., Kirsch, I.R., Ried, T., McPherson, J., Gibbs, R. and Kucherlapati,
R. (2001) A high-resolution map of human chromosome 12. Nature
409: 945-946.
Merscher, S., Funke, B., Epstein, J.A.,
Heyer, J., Puech, A., Lu, M.M., Xavier, R.J., Demay, M.B., Russell,
R.G., Factor, S., Tokooya, K., St. Jore, B., Lopez, M., Pandita,
R.K., Lia, M., Carrion, D., Schorle, H., Kobler, J.B., Scambler,
P., Wynshaw-Boris, A., Skoultchi, A.I., Morrow, B.E. and Kucherlapati,
R. (2001) TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge
syndrome. Cell 104: 619-629.
Costa RM, Federov NB, Kogan JH, Murphy
GG, Stern J, Ohno M, Kucherlapati R, Jacks T, Silva AJ. (2002) Mechanism
for the learning deficits in a mouse model of neurofibromatosis
type 1. Nature 415:526-30.
Velcich A, Yang W, Heyer J, Fragale
A, Nicholas C, Viani S, Kucherlapati R, Lipkin M, Yang K, Augenlicht
L. (2002) Colorectal cancer in mice genetically deficient in the
mucin Muc2. Science 295:1726-9.
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